ArticleExperimental hematology & oncology2024
Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma.
Article in Experimental hematology & oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 26 citations in OpenAlex.
- Neutrophil extracellular traps in tumor progression: from mechanistic insights and regulatory factors to clinical detection and diagnosis.Journal of molecular medicine (Berlin, Germany) · 2026Review
- The emerging role of neutrophil extracellular traps in liver diseases: a narrative review.Medical molecular morphology · 2026Review
- Hepatocellular carcinoma metastasis-immune microenvironment crosstalk: emerging mechanisms and immunotherapy.Cellular & molecular biology letters · 2026Review
- Spatiotemporal heterogeneity of neutrophil extracellular traps in hepatocellular carcinoma microenvironment and targeted therapy progress.Journal of translational medicine · 2026Review
- Dual roles of neutrophil extracellular traps in tumors: From pro-metastatic mechanisms to immunotherapeutic strategies (Review).Oncology letters · 2026Review
- Emerging role of proteomics in advancing diagnosis, prognosis, and treatment of liver cancer.Liver research (Beijing, China) · 2026Review
- Liver-Targeted Gallium-Polyphenol Network by Disrupting the ROS/NETs/PANoptosis Axis for Precision Acute Liver Injury Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Single-cell transcriptome analysis identifies neutrophil-related prognostic signatures in hepatocellular carcinoma.Journal of gastrointestinal oncology · 2026Article
- Neutrophil Extracellular Traps in Cancer Metastasis: From Mechanistic Understanding to Targeted Therapy.Current oncology (Toronto, Ont.) · 2026Review
- The Molecular Network of Neutrophil Extracellular Traps in Hepatocellular Carcinoma: Biogenesis, Function, and Therapeutic Implications.Molecules (Basel, Switzerland) · 2026Review
- HBV reprograms the tumor microenvironment in hepatocellular carcinoma: mechanisms and therapeutic implications.Clinical and experimental medicine · 2026Review
- Spatiotemporal dynamics of tumor-associated neutrophils: bridging the gap between cancer progression and immunotherapy.Molecular cancer · 2026Review
- Neutrophil extracellular traps in tumor microenvironment for radiotherapy: friend or foe?Frontiers in immunology · 2026Review
- LAG3-centered multiplex immune profiling as a prognostic biomarker in hepatocellular carcinoma patients receiving Anti-PD-1 antibodies plus lenvatinib therapy.Frontiers in oncology · 2026Article
- Peri-interventional neutrophil extracellular traps and immune surveillance in hepatocellular carcinoma: mechanisms, biomarkers, and recurrence after liver resection or thermal ablation.Frontiers in oncology · 2026Review
- Reprogrammed Fibrotic Niche Fuels Lung Cancer Initiation and Reciprocal Remodeling.International journal of biological sciences · 2026Review
- Advances in Targeting Neutrophil Extracellular Traps as a Promising Approach for Breast Cancer Treatment.Combinatorial chemistry & high throughput screening · 2026Review
- Extracellular matrix stiffness in hepatocellular carcinoma: mechanisms and targeted therapeutic strategies.Frontiers in immunology · 2026Review
- Neutrophil extracellular traps: the hidden driver of gastrointestinal cancer and emerging therapeutic strategies.Frontiers in immunology · 2026Review
- The role of PD‑1/PD‑L1 axis in liver diseases.Clinical and experimental medicine · 2025Review
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundHepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified.
methodsIn silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment.
resultsWe defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1.
conclusionsCirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.